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Journal of Clinical Medicine

Review Belching in Gastroesophageal Reflux : Literature Review

Akinari Sawada 1 , Yasuhiro Fujiwara 1,* and Daniel Sifrim 2 1 Department of , Osaka City University Graduate School of Medicine, Osaka 545-8585, ; [email protected] 2 Wingate Institute of Neurogastroenterology, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AJ, UK; [email protected] * Correspondence: [email protected]

 Received: 4 October 2020; Accepted: 19 October 2020; Published: 20 October 2020  Abstract: Belching is a common phenomenon. However, it becomes bothersome if excessive. Impedance–pH monitoring can classify the belching into two types: gastric belching and supragastric belching (SGB). The former is a physiological mechanism to vent swallowed air from the , whereas the latter is a behavioral disorder. Gastroesophageal reflux disease (GERD) is the most relevant condition in both types of belching. Recent findings have raised awareness that excessive SGB possibly sheds light on the pathogenesis of a part of proton pump inhibitor (PPI) refractoriness in GERD. SGB could cause typical reflux symptoms such as , regurgitation or in two ways: SGB-induced gastroesophageal reflux or SGB-induced esophageal distension. In PPI-refractory GERD, it is important to detect hidden SGB as a cause of reflux symptoms since SGB requires psychological treatment instead of high dose PPIs or pain modulators. In the case of PPI-refractory GERD with excessive SGB, recent studies imply that the combination of a psychological approach and conventional treatment can improve treatment outcome.

Keywords: gastric belching; supragastric belching; epidemiology; impedance-pH monitoring; gastroesophageal reflux disease; non-erosive reflux disease; reflux hypersensitivity; functional heartburn

1. Introduction Belching is defined as “an audible escape of air from the or the stomach into the ” [1]. Although everyone belches, it can be bothersome when excessive and/or triggering reflux symptoms. If patients cannot control belching in public, they often feel embarrassed, which profoundly disturbs their social lives. Such patients understandably seek medical care for their belching symptom. On the other hand, some patients predominantly complain of typical reflux symptoms rather than belching, even though excessive belching itself causes reflux symptoms [2–4]. Due to poor response to proton pump inhibitors (PPIs) therapy, those patients are often referred to specialists as PPI-refractory gastroesophageal reflux disease (GERD) [2,4–6]. Recent studies suggest that hidden SGB is a possible cause of PPI refractoriness in a deceptively large proportion of GERD. SGB has to be diagnosed appropriately as it requires dedicated psychological therapy. This literature review summarizes belching with regard to mechanisms, epidemiology, relevant conditions, and treatment, focusing on the association with GERD.

2. Two Types of Belching: Gastric Belching and Supragastric Belching

2.1. Gastric Belching (GB) GB is a physiological mechanism to vent swallowed air from the stomach. Air-induced distension of the proximal stomach triggers transient lower esophageal relaxation (TLESR), which allows the

J. Clin. Med. 2020, 9, 3360; doi:10.3390/jcm9103360 www.mdpi.com/journal/jcm J. Clin. Med. 2020, 9, x FOR PEER REVIEW 2 of 14

2. Two Types of Belching: Gastric Belching and Supragastric Belching

2.1. Gastric Belching (GB) J. Clin.GB Med. is2020 a , 9physiological, 3360 mechanism to vent swallowed air from the stomach. Air-induced2 of 14 distension of the proximal stomach triggers transient lower esophageal relaxation (TLESR), which gasallows to bethe released gas to be retrogradely released retrogradely to the pharynx to the (Figurespharynx1 (Figuresand2). TLESR1 and 2). is aTLESR vagal is reflex a vagal via reflex the brainstem,via the brainstem, not a local not reflex a local [7]. reflex In detail, [7]. In the detail, vagal athefferent vagal conveys afferent the conveys stretch ofthe cardiac stretch stomach of cardiac to thestomach brainstem to the via brainstem nodose ganglion via nodo andse solitaryganglion nucleus. and solitary Subsequently, nucleus. vagal Subsequently, efferent projecting vagal efferent to LES fromprojecting the brainstem to LES from releases the brainstem nitric oxide releases and vasoactive nitric oxide intestinal and vasoactive peptide, whichintestinal relaxes peptide, the LES which [8]. Duringrelaxes the TLESR, LES esophageal[8]. During TLESR, shortening esophageal often occurs shortening by much often stronger occurs contraction by much stronger of the longitudinal contraction muscleof the longitudinal than circular muscle muscle. than The circular discordance muscle. of Th thesee discordance two muscle of layers these stretches two muscle myenteric layers stretches neurons tomyenteric release nitric neurons oxide, to release which isnitric possibly oxide, involved which is with possibly the mechanism involved with of TLESR the mechanism [9]. of TLESR [9].

FigureFigure 1.1. Gastric belching andand supragastricsupragastric belchingbelching inin impedance–pHimpedance–pH monitoring.monitoring. Each row inin impedance–pHimpedance–pH tracingstracings measures,measures, from thethe bottom,bottom, gastricgastric pH;pH; esophagealesophageal pH atat 55 cmcm aboveabove thethe lowerlower esophageal sphincter sphincter (LES); (LES); and and impedance impedance at at 3, 3,5, 5,7, 7,9, 9,15, 15, and and 17cm 17cm above above the theLES. LES. In GB In ( GBA), (anA), increase an increase of impedance, of impedance, indicating indicating air from air from the thestomach, stomach, moves moves retrogradely retrogradely from from the thedistal distal to the to theproximal proximal esophagus. esophagus. This This GB GB is isimmediately immediately followed followed by by a aliquid liquid reflux reflux episode episode (i.e., retrograderetrograde B impedanceimpedance decrease).decrease). On On the other hand, SGB ((B) startsstarts withwith antegradeantegrade movementmovement ofof impedanceimpedance increase by sucking or air from the pharynx; subsequently, such increase returns to baseline increase by sucking or swallowing air from the pharynx; subsequently, such increase returns to retrogradely by abdominal straining. This SGB induces a liquid reflux episode. Apart from the SGB baseline retrogradely by abdominal straining. This SGB induces a liquid reflux episode. Apart from inducing reflux, there are two other patterns of the relationship between SGB and reflux. (C) shows the SGB inducing reflux, there are two other patterns of the relationship between SGB and reflux. (C) that several SGBs (blue arrowheads) occur during liquid reflux in which an uncomfortable sensation by shows that several SGBs (blue arrowheads) occur during liquid reflux in which an uncomfortable reflux might lead a patient to perform SGBs. (D) shows SGBs (blue arrowheads) without reflux. In this sensation by reflux might lead a patient to perform SGBs. (D) shows SGBs (blue arrowheads) without case, a patient constantly marked heartburn immediately after SGBs, which suggests the SGBs caused reflux. In this case, a patient constantly marked heartburn immediately after SGBs, which suggests reflux symptoms by esophageal distension. Black arrows indicate the movement of air, whereas red the SGBs caused reflux symptoms by esophageal distension. Black arrows indicate the movement of arrows indicate liquid reflux. air, whereas red arrows indicate liquid reflux.

J. Clin. Med. 2020, 9, 3360 3 of 14 J. Clin. Med. 2020, 9, x FOR PEER REVIEW 3 of 14

Figure 2. GastricFigure 2. belching Gastric belching and supragastric and supragas belchingtric belching in HRM in HRM combined combined with with impedance. impedance. These These pictures illustrate GBpictures (A) illustrate and SGB GB ((BA)) inand simultaneous SGB (B) in simultaneous recording recording of impedance of impedance and and HRM. HRM. (A (A) A) AGB GB occurs occurs with liquid reflux during TLESR. GB can be recognized as a common cavity in HRM. The air with liquidevacuates reflux from during the stomach TLESR. to the GB pharynx can be through recognized the relaxed as UES. a common (B) In SGB, cavitythe contraction in HRM. of The air evacuatesthe from diaphragm the stomach generates to negative the pharynx pressure through in the esophagus. the relaxed UES UES.relaxation (B) Inlets SGB, air into the the contraction of the diaphragmesophagus generatesfollowed by expelling negative the pressure air by abdomina in thel straining. esophagus. No peristalsis UESrelaxation is involved with lets the air into the esophagusair followed movement by in SGB. expelling Black arrows the air indicate by abdominal the movement straining. of air whereas No peristalsisred arrows indicate is involved liquid with the reflux. HRM; high resolution manometry, TLESR; transient lower esophageal sphincter relaxation, air movementUES; upper in SGB. esophageal Black arrowssphincter. indicate the movement of air whereas red arrows indicate liquid reflux. HRM; high resolution manometry, TLESR; transient lower esophageal sphincter relaxation, UES; upper2.2. esophageal Supragastric sphincter. Belching (SGB) SGB is a behavioral disorder where a patient sucks or swallows air from the into the 2.2. Supragastricesophagus, Belching immediately (SGB) followed by expelling it through the pharynx (Figures 1 and 2). Regarding SGB isits physiological a behavioral mechanism, disorder the where diaphragm a patient contracts sucks to generate or swallows negative pressure air from in the the esophagus mouth into the (thoracic cavity). The upper esophageal sphincter (UES) relaxes, letting air into the esophagus (i.e., esophagus,suck) immediately from the pharynx followed due to by the expelling pressure gradient. it through Afterwards, the pharynx the air is(Figures emitted retrogradely1 and2). Regarding into its physiologicalthe pharynx, mechanism, increasing the gastric diaphragm and esophageal contracts pressure to generateby abdominal negative straining pressure [10]. Apart in from the air esophagus (thoracic cavity).sucker type, The a upper minority esophageal of patients use sphincter the pharynge (UES)al pump relaxes, (i.e., letting swallow) air instead into the for esophagusthe intake of (i.e., suck) from the pharynxair. due to the pressure gradient. Afterwards, the air is emitted retrogradely into the A small number of SGB and GB can be seen in healthy asymptomatic subjects. [11,12]. SGB pharynx, increasingbecomes bothersome gastric when and excessive esophageal as it pressurecan impair byquality abdominal of life [13] strainingand induce [10pathological]. Apart from air sucker type,gastroesophageal a minority of reflux patients [3,6,14]. use We the previously pharyngeal proposed pump ≤13 (i.e., episodes/24 swallow) h as insteadthe normal for value the intakeof of air. A smallSGB number [11]. However, of SGB it andshould GB be can taken be into seen consider in healthyation that asymptomatic personal factors subjects. can alter [the11 ,threshold12]. SGB becomes bothersomefor when feeling excessive belching as as irritating. it can impair In many quality cases, ofpatients life [13 ca]n and identify induce warning pathological symptoms gastroesophageal such as throat/chest/abdominal discomfort to trigger SGB [3]. Presumably, patients learn the behavior to try reflux [3,6,14]. We previously proposed 13 episodes/24 h as the normal value of SGB [11]. However, to ease such an unpleasant sensation in≤ some way, and with time it turns into a subconscious act. We it should besometimes taken into encounter consideration patients who that remember personal the factorsexact moment can alter or time the wh thresholden they began for feelinghaving belching as irritating. In many cases, patients can identify warning symptoms such as throat/chest/abdominal discomfort to trigger SGB [3]. Presumably, patients learn the behavior to try to ease such an unpleasant sensation in some way, and with time it turns into a subconscious act. We sometimes encounter patients who remember the exact moment or time when they began having excessive SGB. In such cases, stressful life events might precipitate SBG. In animal experiments, Lang et al. found that esophageal distension can trigger a reflex of inhaling air followed by belching via vagal and esophageal tension/mucosal mechanoreceptors [15]. In light of this finding, a limited part of SGB might be a reflex rather than a behavior, especially when gas reflux causes the initial esophageal distension. J. Clin. Med. 2020, 9, 3360 4 of 14

Psychological factors can influence the frequency of SGB. Bredenoord et al. showed that patients have more SGBs when aware of impedance recording, whilst distraction by filling in questionnaires or speaking can reduce the number of SBGs [16]. Additionally, SGB is hardly observed during sleeping [17]. RegardingJ.personality, Clin. Med. 2020, 9, x FOR our PEER previous REVIEW study found that patients with excessive4 SGB of 14 showed lower levels of neuroticismexcessive (i.e.,SGB. In tend such cases, to less stressful worry life events about might symptoms) precipitate SBG. and In animal the same experiments, level Lang of hypervigilance (i.e., tend not toet be al. found too alert that esophageal for bodily distension sensation) can trigger compared a reflex of inhaling to healthy air followed subjects by belching [3]. via vagal nerves and esophageal tension/mucosal mechanoreceptors [15]. In light of this finding, a limited part of SGB might be a reflex rather than a behavior, especially when gas reflux causes the 3. Conceptual Changeinitial esophageal of Belching distension. Disorders and in Rome Diagnostic Criteria Psychological factors can influence the frequency of SGB. Bredenoord et al. showed that patients Excessivehave belching more SGBs was when initially aware of impedance thought recording, to be whilst a consequence distraction by filling of in aerophagiaquestionnaires (frequent air swallowing) [18or]. speaking Therefore, can reduce Rome the II number defined of SBGs excessive [16]. Additionally, belching SGB as aispart hardly of observed “Aerophagia”. during The advent of intraluminalsleeping impedance [17]. monitoring enabled us to assess both the type and movement of bolus Regarding personality, our previous study found that patients with excessive SGB showed lower in the esophaguslevels (i.e., of neuroticism gas or (i.e., liquid, tend to andless worry antegrade about symptoms) or retrograde and the same level movement) of hypervigilance [19, 20]. With this technique, Bredenoord(i.e., tend not et to al. be too found alert for a bodily novel sensation) type of compared belching to healthy named subjects supragastric [3]. belching (SGB) [21]. This finding brought3. Conceptual research Change of about Belching belching Disorders and into Aerophagia the next in Rome level Diagnostic because, Criteria until this study, all the belching had beenExcessive considered belching as was gastric initially belching.thought to be Consequently,a consequence of aerophagia Rome III (frequent expanded air the disease concept by addingswallowing) “unspecified [18]. Therefore, excessive Rome II belching defined excessive (i.e., excessive belching as belchinga part of “Aerophagia”. without air The swallowing)” as advent of intraluminal impedance monitoring enabled us to assess both the type and movement of the other subcategorybolus in the apart esophagus from (i.e., “aerophagia”, gas or liquid, and and antegrade renamed or retrograde the disorder movement) as [19,20]. “Belching With this Disorders” [22]. At that time, thetechnique, two terms, Bredenoord “aerophagia” et al. found a novel and type “SGB”, of belching were named used supragastric in a bewildering belching (SGB) way [21]. since SGB was This finding brought research about belching into the next level because, until this study, all the thought to be foundbelching only had inbeen “aerophagia” considered as gastric [21]. belching. However, Consequently the two, Rome disorders III expanded have the been disease segregated from each other recentlyconcept because by adding they“unspecified have excessive distinctive belching features (i.e., excessive or belching physiology. without air In swallowing)” aerophagia, esophageal peristalsis propelsas theswallowed other subcategory air, apart which from “aerophagia”, ends upaccumulating and renamed the disorder in the as “Belching intestine Disorders” and colon. It mainly [22]. At that time, the two terms, “aerophagia” and “SGB”, were used in a bewildering way since SGB manifests itselfwas as ,thought to be abdominalfound only in “aerophagia” distention [21] and. However, , the two disorders although have been some segregated patients complain of PPI refractoryfrom GERD each other symptoms recently because [4]. they On have the otherdistinctive hand, features SGB or physiology. does not In involve aerophagia, any esophageal esophageal peristalsis propels swallowed air, which ends up accumulating in the intestine and colon. peristalsis, andIt swallowed mainly manifests air itself does as bloating, not reach abdominal the stomachdistention and [23 constipation,,24]. Nevertheless, although some aerophagiapatients still lacks clear diagnosticcomplain criteria of toPPI distinguish refractory GERD from symptoms normal [4]. On air the swallowing. other hand, SGB The does latest not involve Rome any IV removed the esophageal peristalsis, and swallowed air does not reach the stomach [23,24]. Nevertheless, term “Aerophagia”aerophagia from still “Belching lacks clear diagnostic disorders” criteria in to whichdistinguish belching from normal was air simplyswallowing. classified The latest into excessive GB and SGB onRome the IV basis removed of the the term origin “Aerophagia” of the gas from [ 1“Belching] (Figure disorders”3). in which belching was simply classified into excessive GB and SGB on the basis of the origin of the gas [1] (Figure 3).

Figure 3. ConceptualFigure 3. changeConceptual of change Belching of Belching disorders disorders and and Aerophagia Aerophagia in Rome in diagnostic Rome criteria. diagnostic GB; criteria. GB; gastric belching,gastric SGB; belching, supragastric SGB; supragastric belching. belching.

4. Epidemiology

There are several studies reporting the prevalence of belching symptom in the general population, which ranges from 6.7% to 28.8% [25–28]. Subjects are more likely to complain of belching symptom when having concomitant typical reflux symptoms (i.e., heartburn and/or regurgitation) (Table1). In GERD patients, the prevalence of belching ranges widely from 4.1–75.6% [14,29–33]. Interestingly, Klauser et al. [29] showed no difference in the prevalence of belching between normal and pathological acid exposure in GERD. It is important to note that these epidemiological studies include both types of belching (i.e., GB and SGB) due to interview-based survey. Besides, heterogeneous definitions of excessive belching and GERD can influence the results significantly. J. Clin. Med. 2020, 9, 3360 5 of 14

Table 1. Prevalence of belching symptom.

Prevalence of Prevalence of Overall Number of People Belching Belching Author Country Study Subjects Prevalence of Definition of GERD Surveyed (n) Symptom Symptom with Belching without GERD GERD General Westbrook et al. [25] Australia 2300 6.7% population General 11.5% 23.2% Heartburn and/or Bor et al. [26] Turkey 630 15.9% population (n = 393) (n = 237) regurgitation General 12.6% 37.5% Heartburn and/or Rey et al. [27] Spain 2500 20.5% population (n = 1709) (n = 791) regurgitation 28.8% 26.3% 58.5% Li et al. [28] Outpatients 15283 RDQ score > 12 (n = 13282) (n = 12257) (n = 1025) Kessing et al. [14] Netherland GERD 90 - - 75.6% Reflux symptoms Klauser et al. [29] Germany GERD 304 44.7% Esophageal symptom Heartburn, regurgitation, Dore et al. [30] Italy GERD 266 - - 26.3% or Heartburn, Yarandi et al. [31] Iran GERD 1522 - - 4.1% regurgitation and dysphagia Heartburn, regurgitation, or Ribolsi et al. [32] Italy GERD 573 - - 62.7% noncardiac chest pain Positive DeMeester score (>14.2), Lin et al. [33] USA GERD 180 70% endoscopic , or Barrett’s esophagus RDQ; Reflux Disease Questionnaire. J. Clin. Med. 2020, 9, 3360 6 of 14

As for the prevalence of SGB, our previous studies found that 3.4% of patients referred to a tertiary GI physiology unit had excessive SGB [11], and the prevalence in PPI-refractory GERD patients differs between regions as the Japanese (18.5%) had lower prevalence of excessive SGB compared to the British (36.1%) [12].

5. Belching and Gastroesophageal Reflux Disease J. Clin.Figure Med. 20204 illustrates, 9, x FOR PEER the REVIEW relationship between belching and GERD and other relevant conditions.8 of 14

Figure 4. Factors affecting Gastric belching and Supragastric belching. GERD; gastroesophageal reflux disease,Figure 4. FD; Factors functional affecting dyspepsia, Gastric belching PUD; peptic and Supragastric ulcer disease, belching. LARS; laparoscopic GERD; gastroesophageal anti-reflux surgery. reflux disease, FD; functional dyspepsia, PUD; , LARS; laparoscopic anti-reflux surgery. 5.1. Gastric Belching (GB) 7. ClinicalTwenty-four-hour Approach and impedance–pH Treatment for monitoring Belching showed more frequent air swallowing and GBs in GERD compared to normal subjects, where the number of GBs moderately correlates to the number of7.1. air Clinical swallowing Approach [34 to]. Excessive Bravi et al.Belching found that patients with PPI-refractory GERD have much more prandialPatients aerophagia with troublesome and postprandial belching GB can than be divided PPI responders into two [4 groups:]. However, GB- or GB SGB-predominant might not cause liquidtype. Li reflux et al. despite found sharing that both the commongroups have reflux si mechanismmilar reflux (i.e., profile TLESR) and [34 air,35 swallow,], as gas reflux but the precedes SGB- liquidpredominant reflux in type only showed up to half more of acidbelching mixed episodes (i.e., gas than and liquid)GB-predominant reflux [20,36 type]. Its [62]. causal With link respect remains to tothe be symptom, elucidated. Kessing et al. found the severity of belching symptom depends on the number of SGBs, not GBs [14]. The number or severity of belching could provide clinicians with a hint on the type of 5.2. Supragastric Belching (SGB) belching (i.e., SGB tends to be repetitive whereas GB tend to be single isolated events). However, impedance–pHSGB can induce monitoring, reflux, the a gold mechanism standard of modali which isty, unclear is often (Figure necessary1B). Therefor precise are three diagnosis. possibilities as follows: (1) SGB-induced esophageal distension might provoke A TLESR [37,38], (2) AN INCREASE IN7.2. abdominal Clinical Approach pressure to Hidden might bringSGB in up PPI-Refractory the gastric contents GERD through the LES, (3) TLESR might elicit a reflex of UES relaxation, which IN TURN lets the air into the esophagus [39]. Glasinovic et al. In PPI-refractory GERD, many patients do not report belching symptom even when SGB is a showed that 26% of total acid exposure time is caused by SGB-induced reflux in GERD patients with culprit of reflux symptoms. Therefore, clinicians have to pay attention to impedance tracing so that excessive SGB [3]. This study also showed improvement of acid exposure by the reduction of SGB, hidden SGB is not overlooked. As approximately 50–60% of the SGBs exist close to reflux episodes which indicates that SGB itself elicits reflux and does not coincidentally occur close to reflux. [2,6], manual editing of automatic analysis of all reflux episodes can identify pathologic SGB. It is 5.3.important Impact to of Supragastricevaluate to what Belching extent (SGB) SGB on causes PPI-Refractory acid exposure GERD or reflux symptom.

7.3. TreatmentRecent studies for Gastric have Belching increasingly raised awareness of potential involvement of SGB on reflux symptoms (not belching symptom) in a fairly large proportion of PPI-refractory GERD. Yadlapatiet al. [5] Treatment for GB should target air swallowing and/or TLESR. showed as much as 42% of PPI-refractory GERD patients have pathological SGB. Our study [2] found To suppress air swallowing, it is worth trying to provide instruction to eat slowly and avoid carbonated drinks. Several studies showed that PPI therapy improves belching symptom [30,63–65], except for one study reporting no benefit [66]. The effect of PPIs on reflux symptoms might stop air swallowing as a response to chest/abdominal discomfort. Anti-reflux surgery reduces the number of TLESRs [44]. Besides, gamma aminobutyric acid receptor type B (GABAB) receptor agonist, baclofen, can alleviate belching symptom by reducing the number of TLESRs [67] and increasing LES pressure [68]. However, baclofen has a side effect of drowsiness, and thus, is not widely used. , peripherally acting as a GABAB receptor agonist, showed its ability to reduce TLESR with little central nervous system effect [69]. Nevertheless, it has never been launched.

J. Clin. Med. 2020, 9, 3360 7 of 14 that prevalence varies between reflux phenotypes with 37.7% in non-erosive reflux disease (NERD) (i.e., acid exposure time > 6%), 39.7% in reflux hypersensitivity (RH) (i.e., acid exposure time < 4% and positive symptom reflux association) and 22% in functional heartburn (FH) (i.e., acid exposure time < 4% and negative symptom reflux association). More importantly, SGB is potentially responsible for approximately 40% of typical reflux symptoms (heartburn, regurgitation or chest pain) in RH [2], and the severity of reflux symptoms correlates to the extent of SGB positively [14]. These studies imply that treatment for SGB is required to relieve reflux symptoms in a part of PPI-refractory GERD. Presumably, SGB provokes typical reflux symptoms in two ways: (1) inducing reflux and (2) air-induced esophageal distension (Figure1D). Takeda et al. found that esophageal balloon distension triggers heartburn, and the likelihood of triggering the symptom depends on the extent of distension [40]. The ethnic/racial difference can influence the perception of SGB, as SGB is less associated with reflux symptoms in Japanese than in British [12].

5.4. Belching after Anti-Reflux Surgery

5.4.1. Laparoscopic Fundoplication Laparoscopic (LNF) is one of the most common procedures for GERD, which creates a 360◦ wrap of the stomach around the esophagogastric junction (EGJ) and repairs the crura if necessary. By tightening the EGJ, LNF eliminates reflux as well as GBs. However, LNF makes patients feel difficult to belch and can produce other gas-related symptoms including bloating or flatulence [41–43]. These discomforts presumably lead the patients to perform SGB as a futile attempt to belch and end up increasing the number of SGBs postoperatively [44]. Regarding laparoscopic partial fundoplication (LPF), which constructs a looser wrap (e.g., 270◦ posterior wrap (Toupet)), it can reduce gastroesophageal reflux similar to LNF and lessen postoperative gas-related symptoms, with the ability to belch remaining. However, LPF also increases the number of SGBs [45,46].

5.4.2. Magnetic Sphincter Augmentation Device (LINX Reflux Management System) Magnetic sphincter augmentation device (MSA) is made up of titanium beads with a magnetic core in a ring shape, which is laparoscopically placed around the LES. MSA aims to reinforce the weak LES to resist the gastric pressure (i.e., gastroesophageal reflux) without interfering with the passage of swallowed food bolus. Previous meta-analyses showed MSA is superior to LNF concerning preservation of the ability to belch, with a similar extent of reflux symptom improvement [47,48]. Several case series also reported that almost all patients kept the ability to belch postoperatively [49–51]. However, there are few studies to objectively assess influence of MSA on belching using impedance monitoring.

6. Belching and Other Relevant Conditions

6.1. Functional Dyspepsia Up to 80% of functional dyspepsia (FD) patients complain of belching symptom [33,52–54]. According to a study by Conchillo et al., a high prevalence of belching symptom in FD is probably attributed to more frequent air swallowing compared to healthy subjects [55]. Belching symptom was associated with lower quality of life and more weight loss in patients with FD [52]. It could be explained by higher sensitivity to gastric dilatation in FD patients with concomitant belching symptom than without [53]. However, it remains uncertain if epigastric discomfort causes air swallowing or vice versa. The two factors might interact mutually to increase distressing symptoms. Interestingly, FD shows less correlation between belching symptom and acid reflux than GERD, and PPIs do not improve belching in FD unlike that in GERD [33]. Although little is known about the association between FD and SGB, patients with excessive SGB often identify abdominal discomfort as a warning signal [3]. J. Clin. Med. 2020, 9, 3360 8 of 14

6.2. Globus Globus is a functional gastrointestinal disorder consisting of a persistent or intermittent lump sensation in the throat [56]. Patients with globus had higher prevalence of pathological SGB and aerophagia than GERD patients [57]. There might be a causal link between SGB and globus as some patients recognize throat discomfort as a warning signal for SGB [58].

6.3. Bariatric Surgery (Sleeve Gastrectomy) Sleeve gastrectomy is one of the bariatric surgeries, which removes a generous portion of the stomach on the greater curvature side to create a tubular gastric pouch. Burgerhart et al. showed laparoscopic sleeve gastrectomy (LSG) almost doubled the number of GBs (from 29.7 to 59.5/24 h) despite the decrease of liquid and air swallows, whereas the number of SGBs did not alter [59]. As LSG is known to increase esophageal acid exposure with the decrease of LES pressure [60], LSG might increase GB by the anatomical change of the stomach (i.e., lack of gastric fundus and small accommodation capacity) and the weakened LES.

6.4. Miscellaneous Conditions Various disorders causing distressing symptoms around the chest and (i.e., peptic ulcer disease, pancreatitis, pectoris and symptomatic cholelithiasis) are reported to manifest in belching symptom [61]. However, their causal link remains vague.

7. Clinical Approach and Treatment for Belching

7.1. Clinical Approach to Excessive Belching Patients with troublesome belching can be divided into two groups: GB- or SGB-predominant type. Li et al. found that both groups have similar reflux profile and air swallow, but the SGB-predominant type showed more belching episodes than GB-predominant type [62]. With respect to the symptom, Kessing et al. found the severity of belching symptom depends on the number of SGBs, not GBs [14]. The number or severity of belching could provide clinicians with a hint on the type of belching (i.e., SGB tends to be repetitive whereas GB tend to be single isolated events). However, impedance–pH monitoring, a gold standard modality, is often necessary for precise diagnosis.

7.2. Clinical Approach to Hidden SGB in PPI-Refractory GERD In PPI-refractory GERD, many patients do not report belching symptom even when SGB is a culprit of reflux symptoms. Therefore, clinicians have to pay attention to impedance tracing so that hidden SGB is not overlooked. As approximately 50–60% of the SGBs exist close to reflux episodes [2,6], manual editing of automatic analysis of all reflux episodes can identify pathologic SGB. It is important to evaluate to what extent SGB causes acid exposure or reflux symptom.

7.3. Treatment for Gastric Belching Treatment for GB should target air swallowing and/or TLESR. To suppress air swallowing, it is worth trying to provide instruction to eat slowly and avoid carbonated drinks. Several studies showed that PPI therapy improves belching symptom [30,63–65], except for one study reporting no benefit [66]. The effect of PPIs on reflux symptoms might stop air swallowing as a response to chest/abdominal discomfort. Anti-reflux surgery reduces the number of TLESRs [44]. Besides, gamma aminobutyric acid receptor type B (GABAB) receptor agonist, baclofen, can alleviate belching symptom by reducing the number of TLESRs [67] and increasing LES pressure [68]. However, baclofen has a side effect of drowsiness, and thus, is not widely used. Lesogaberan, peripherally acting as a GABAB receptor agonist, showed its ability to reduce TLESR with little central nervous system effect [69]. Nevertheless, it has never been launched. J. Clin. Med. 2020, 9, 3360 9 of 14

In most cases, patients suffer from both excessive GB and reflux symptom. In addition to the eating habit modification, the therapeutic options can be optimized on the basis of reflux phenotype. For patients with severe erosive reflux disease or NERD, laparoscopic fundoplication or a maximum dose of PPI plus baclofen would be the first choice. For RH and FH patients (normal acid exposure), adding baclofen to their mainstream therapy, which is pain modulators, is likely to be beneficial as long as patients can tolerate its side effect. In functional dyspepsia, several drugs shows a suppressive effect on belching symptom, such as rifaximin [70], acotiamide (acetylcholinesterase inhibitor) [71,72], rebamipide (mucosal protective agents), and (H2 receptor antagonist) [73].

7.4. Treatment for Supragastric Belching SGB benefits from psychological therapy to unlearn or interrupt the acquired behavioral. Dedicated cognitive behavior therapy [3,74,75] or speech therapy [76,77] have established its efficacy on SGB. Speech therapy improves the severity of belching symptom in 83% of SGB patients, whereas CBT reduces the number of SGBs objectively by >50% in half of patients [3]. These two treatments share the common concept consisting of cognitive and behavioral components. For instance, our CBT has five sessions. In the cognitive part, firstly therapists explain the mechanism of SGB so that patients can understand SGB is a subconscious but deliberate behavior. We should be careful not to make patients feel blamed in this process. Otherwise, it will impact adherence to the treatment negatively. Secondly, a warning signal (premonitory sensations) should be identified, which causes patients to commence SGB to deal with the sensation. In most cases, throat, chest, or abdominal discomfort are identified as a warning signal, which can be used for a cue to start exercise to stop SGB as below. Additionally, the thought that SGB is useful to ease that discomfort needs to be corrected. In the behavioral part, therapists instruct patients in the use of (1) diaphragmatic , and (2) mouth opening/tongue position to make it physically impossible to perform SGB. Diaphragmatic breathing inhales and exhales, spending 3 s in each phase by moving the abdominal wall, not the thoracic wall. Patients need to breathe through the mouth with opening moderately and place the tongue behind the top front teeth. These procedures should be trained at least twice per day for 3–5 min in a supine or sitting position. Once patients get used to the breathing technique, they are encouraged to use it as often as possible, especially when noticing a warning signal or commencing a bunch of SGBs. Our previous study found a lower number of SGBs, lower hypervigilance, and higher CBT proficiency (i.e., possible to identify a warning signal, better acceptance and adherence to CBT), which are predictive factors for better outcome, and the therapeutic effect of CBT sustains for at least 12 months [58]. Concerning , a case has been reported that a combination of baclofen and gabapentin alleviates SGB [78]. On the other hand, a randomized controlled trial shows baclofen does not decrease the number of SGBs [79].

7.5. Treatment Implication for SGB With PPI-Refractory GERD In this setting, SGB is possibly required for improving typical reflux symptoms along with the current mainstream therapy for PPI refractoriness [2,5]. On the basis of relevant literatures, we here propose a possible therapeutic approach for each reflux phenotype with excessive SGB.

7.5.1. Excessive SGB with Severe Erosive Esophagitis or NERD Sole CBT probably cannot reduce acid exposure to the physiological range in this scenario, although it depends to what extent SGB-induced reflux accounts for acid exposure time. In fact, a previous study showed CBT decreases acid exposure time significantly, however, it was inadequate to normalize it [3]. Therefore, it would be reasonable to perform ARS first to protect damaged esophageal mucosa and subsequently add CBT for SGB, as ARS might further increase the number of SGBs [44]. J. Clin. Med. 2020, 9, 3360 10 of 14

7.5.2. Excessive SGB with RH Excessive SGB possibly accounts for approximately 40% of typical reflux symptoms [2]. Considering SGB hardly responds to pain modulators or PPIs, dual therapy (i.e., pain modulators and CBT) might be beneficial for easing reflux symptoms. However, further study is warranted to see which treatment is the best, sole CBT, pain modulators or dual therapy.

7.5.3. Excessive SGB with FH FH has a lower prevalence of excessive SGB than RH [2], however, there is a possibility that SGB-induced distension causes reflux symptoms in FH like RH. However, there is no study to assess the association between SGB and reflux symptoms in FH. If that is the case, dual therapy of CBT and pain modulators might be effective.

8. Conclusions Belching can be classified into GB and SGB by impedance monitoring. SGB causes not only belching symptom but reflux symptoms by esophageal distension. As recent studies stress a role of SGB on PPI refractoriness in GERD, SGB should be carefully detected even when patients do not complain of belching symptom much. The therapeutic options for GB and SGB are still limited as there is little treatment for air swallowing, and no alternative to psychological treatment for SGB although up to 50% of patients do not respond to CBT. Further study is required to tackle these problems.

Author Contributions: Conceptualization, A.S. and Y.F.; Methodology, A.S. and Y.F.; Investigation, A.S.; Data Curation, A.S.; Writing-Original Draft Preparation, A.S.; Writing-Review & Editing, Y.F. and D.S.; Supervision, Y.F. All authors have read and agreed to the published version of the manuscript. Funding: This research received no external funding. Conflicts of Interest: All the authors declare no conflict of interest with this review.

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